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Cylindrocyclophanes with proteasome inhibitory activity from the Cyanobacterium Nostoc sp.

ABSTRACT: Material collected from a parkway in the city of Chicago afforded the isolation of a Nostoc species (UIC 10022A). The extract of this strain displayed significant inhibition of the 20S proteasome as well as antiproliferative activity against HT29, MCF7, NCI-H460, and SF268 cancer cell lines. A standardized dereplication protocol allowed for the rapid identification of three known (11-13) and nine new (1-9) chlorinated cylindrocyclophanes from less than 100 mg of organic extract. Scale-up isolation of 1-9 and 11-13 from a larger extract was guided by LC-UV-MS data. In addition, KBr enrichment of the culture media afforded the isolation of a brominated cylindrocyclophane (10). Biological evaluation of 1-5, 9, and 10-13 revealed a large range of activity against the 20S proteasome and allowed the determination of preliminary structure-activity relationships of the cylindrocyclophane pharmacophore.

SUBMITTER: Chlipala GE

PROVIDER: S-EPMC2964865 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Cylindrocyclophanes with proteasome inhibitory activity from the Cyanobacterium Nostoc sp.

Chlipala George E GE Sturdy Megan M Krunic Aleksej A Lantvit Daniel D DD Shen Qi Q Porter Kyle K Swanson Steven M SM Orjala Jimmy J

Journal of natural products 20100901 9

Material collected from a parkway in the city of Chicago afforded the isolation of a Nostoc species (UIC 10022A). The extract of this strain displayed significant inhibition of the 20S proteasome as well as antiproliferative activity against HT29, MCF7, NCI-H460, and SF268 cancer cell lines. A standardized dereplication protocol allowed for the rapid identification of three known (11-13) and nine new (1-9) chlorinated cylindrocyclophanes from less than 100 mg of organic extract. Scale-up isolati ...[more]

PMID: 20825206

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Project description:Ice-binding proteins (IBPs) have been identified in numerous polar algae and bacteria, but so far not in any cyanobacteria, despite the abundance of cyanobacteria in polar regions. We previously reported strong IBP activity associated with an Antarctic Nostoc species. In this study, to identify the proteins responsible, as well as elucidate their origin, we sequenced the DNA of an environmental sample of this species, designated Nostoc sp. HG1, and its bacterial community and attempted to identify IBPs by looking for known IBPs in the metagenome and by looking for novel IBPs by tandem mass spectrometry (MS/MS) proteomics analyses of ice affinity-purified proteins. The metagenome contained over 116 DUF3494-type IBP genes, the most common type of IBP identified so far. One of the IBPs could be confidently assigned to Nostoc, while the others could be attributed to diverse bacteria, which, surprisingly, accounted for the great majority of the metagenome. Recombinant Nostoc IBPs (nIBPs) had strong ice-structuring activities, and their circular dichroism spectra were consistent with the secondary structure of a DUF3494-type IBP. nIBP is unusual in that it is the only IBP identified so far to have a PEP (amino acid motif) C-terminal signal, a signal that has been associated with anchoring to the outer cell membrane. These results suggest that the observed IBP activity of Nostoc sp. HG1 was due to a combination of endogenous and exogenous IBPs. Amino acid and nucleotide sequence analyses of nIBP raise the possibility that it was acquired from a planctomycete.IMPORTANCE The horizontal transfer of genes encoding ice-binding proteins (IBPs), proteins that confer freeze-thaw tolerance, has allowed many microorganisms to expand their ranges into polar regions. One group of microorganisms for which nothing is known about its IBPs is cyanobacteria. In this study, we identified a cyanobacterial IBP and showed that it was likely acquired from another bacterium, probably a planctomycete. We also showed that a consortium of IBP-producing bacteria living with the Nostoc contribute to its IBP activity.

Project description:Swinholides are 42-carbon ring polyketides with a 2-fold axis of symmetry. They are potent cytotoxins that disrupt the actin cytoskeleton. Swinholides were discovered from the marine sponge Theonella sp. and were long suspected to be produced by symbiotic bacteria. Misakinolide, a structural variant of swinholide, was recently demonstrated to be the product of a symbiotic heterotrophic proteobacterium. Here, we report the production of swinholide A by an axenic strain of the terrestrial cyanobacterium Nostoc sp. strain UHCC 0450. We located the 85-kb trans-AT polyketide synthase (PKS) swinholide biosynthesis gene cluster from a draft genome of Nostoc sp. UHCC 0450. The swinholide and misakinolide biosynthesis gene clusters share an almost identical order of catalytic domains, with 85% nucleotide sequence identity, and they group together in phylogenetic analysis. Our results resolve speculation around the true producer of swinholides and demonstrate that bacteria belonging to two distantly related phyla both produce structural variants of the same natural product. In addition, we described a biosynthesis cluster from Anabaena sp. strain UHCC 0451 for the synthesis of the cytotoxic and antifungal scytophycin. All of these biosynthesis gene clusters were closely related to each other and created a group of cytotoxic macrolide compounds produced by trans-AT PKSs of cyanobacteria and proteobacteria.IMPORTANCE Many of the drugs in use today originate from natural products. New candidate compounds for drug development are needed due to increased drug resistance. An increased knowledge of the biosynthesis of bioactive compounds can be used to aid chemical synthesis to produce novel drugs. Here, we show that a terrestrial axenic culture of Nostoc cyanobacterium produces swinholides, which have been previously found only from marine sponge or samples related to them. Swinholides are polyketides with a 2-fold axis of symmetry, and they are potent cytotoxins that disrupt the actin cytoskeleton. We describe the biosynthesis gene clusters of swinholide from Nostoc cyanobacteria, as well as the related cytotoxic and antifungal scytophycin from Anabaena cyanobacteria, and we study the evolution of their trans-AT polyketide synthases. Interestingly, swinholide is closely related to misakinolide produced by a symbiotic heterotrophic proteobacterium, demonstrating that bacteria belonging to two distantly related phyla and different habitats can produce similar natural products.

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Cylindrocyclophanes with proteasome inhibitory activity from the Cyanobacterium Nostoc sp.

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Cylindrocyclophanes with proteasome inhibitory activity from the Cyanobacterium Nostoc sp.

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